Specific aims of the proposed research are the study of new experimental directions for successful elimination of malignant hematological disorders and particularly of B-cell leukemia/lymphoma variants. The tumor model to be studied is the spontaneous BALB/c murine B-cell leukemia (BCL1) recently described by Slavin and Strober. This tumor model resembles the malignant human prolymphocytic leukemia/lymphoma. Inoculation of BALB/c or their F1 hybrids with BCL1 causes enormous splenomegaly (x50), leukemia (up to 700,000/mm3 b-lymphocytes in the peripheral blood) and death in 100% of recipients. Tumor eradication will be attempted by combining a number of different approaches along two main directions based on successful preliminary studies. The first approach consists of the use of allogeneic bone marrow transplantation following conditioning of tumor-bearing recipients with fractionated total lymphoid irradiation (TLI). This form of radiotherapy results in potent immunosuppression, reduces tumor load and results in generation of specific and nonspecific suppressor cells. TLI permits successful engraftment of histoincompatible marrow allografts without overt graft versus host disease (GVHD). Our preliminary data suggest that incompatible, unlike syngeneic, cells may exert a potent graft vs. leukemia (GVL) effect without GVHD in mice showing bilateral tolerance of host to graft and graft to host. Clinical administration of high-dose, tumoricidal levels of chemoradiotherapy followed by protective, allogeneic marrow is a potential realistic goal following our proposed experiments. In the second approach we will study therapeutic protocols that depend upon the use of tumor-specific antibodies. The BCL1 tumor cells bear monoclonal IgM 1ambda molecules that can be recognized in a specific way by anti-idiotypic (anti-Id) antibodies. Idiotypic determinants on tumor cells will serve as targets for specific immunotherapy. Anti-Ed antibodies and toxin-anti-Id conjugates will be used to generate idiotype-specific suppression of tumor development and specific elimination of tumor cells in-vivo. Anti-Id antibodies will be generated by affinity purification of rabbit anti-mouse antibodies or by the use of hybridoma antibodies. Cure of leukemia will be attempted by combining different cytoreductive protocols, marrow rescue and GVL as well as idiotype specific anti-tumor methods.